Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain

Nahla Zaghloul, Dalibor Kurepa, Mohammad Y. Bader, Nadia Nagy, Mohamed N. Ahmed

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background: Periventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI. Methods: Transgenic mice with specific knockout NF-κB in microglia and colony stimulating factor 1 receptor Cre with floxed IKKβ (CSF-1R Cre + IKKβflox/wt ) were used. Postnatal day 5 (P5) mice underwent sham or bilateral temporary carotid artery ligation followed by hypoxia. After HI insult, inflammatory cytokines, volumetric MRI, histopathology, and immunohistochemistry for oligodendroglia and microglial activation markers were analyzed. Long-term neurobehavioral assessment, including grip strength, rotarod, and open field testing, was performed at P60. Results: We demonstrate that selective inhibition of NF-κB in microglia decreases HI-induced brain injury by decreasing microglial activation, proinflammatory cytokines, and nitrative stress. Rescue of oligodendroglia is evidenced by immunohistochemistry, decreased ventriculomegaly on MRI, and histopathology. This selective inhibition leads to attenuation of paresis, incoordination, and improved grip strength, gait, and locomotion. Conclusion: We conclude that NF-κb activation in microglia plays a major role in the pathogenesis of hypoxic ischemic injury of the immature brain, and its prophylactic inhibition offers significant neuroprotection. Using a specific inhibitor of microglial NF-κB may offer a new prophylactic or therapeutic alternative in preterm infants affected by HI and possibly other neurological diseases in which microglial activation plays a role.

Original languageEnglish (US)
Article number365
JournalJournal of Neuroinflammation
Volume17
Issue number1
DOIs
StatePublished - Dec 2020

Keywords

  • Cerebral palsy
  • Hypoxia ischemia
  • Microglia
  • NF-κB
  • Neuroprotection
  • Oligodendroglia
  • Periventricular leukomalacia
  • White matter brain injury

ASJC Scopus subject areas

  • General Neuroscience
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain'. Together they form a unique fingerprint.

Cite this